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1.
Toll‐like receptor (TLR) signalling plays an important role in regulating cerebral ischaemia–reperfusion (I/R) injury. Toll‐interacting protein (Tollip) is an endogenous negative modulator of TLR signalling that is involved in several inflammatory diseases. Our previous study showed that Tollip inhibits overload‐induced cardiac remodelling. However, the role of Tollip in neurological disease remains unknown. In the present study, we proposed that Tollip might contribute to the progression of stroke and confirmed this hypothesis. We found that Tollip expression was significantly increased in I/R‐challenged brain tissue of humans, mice and rats in vivo and in primary neurons subjected to oxygen and glucose deprivation in vitro, indicating the involvement of Tollip in I/R injury. Next, using genetic approaches, we revealed that Tollip deficiency protects mice against I/R injury by attenuating neuronal apoptosis and inflammation, as demonstrated by the decreased expression of pro‐apoptotic and pro‐inflammatory genes and the increased expression of anti‐apoptotic genes. By contrast, neuron‐specific Tollip over‐expression exerted the opposite effect. Mechanistically, the detrimental effects of Tollip on neuronal apoptosis and inflammation following I/R injury were largely mediated by the suppression of Akt signalling. Additionally, to further support our findings, a Tollip knockout rat strain was generated via CRISPR‐Cas9‐mediated gene inactivation. The Tollip‐deficient rats were also protected from I/R injury, based on dramatic decreases in neuronal apoptosis and ischaemic inflammation through Akt activation. Taken together, our findings demonstrate that Tollip acts as a novel modulator of I/R injury by promoting neuronal apoptosis and ischaemic inflammation, which are largely mediated by suppression of Akt signalling. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.  相似文献   
2.
目的:探讨TLR4、NF-κBp65及负性调控因子Tollip在TNBS诱导的结肠炎大鼠肠黏膜中的表达。方法:采用免疫组织化学及RT-PCR方法比较正常组与模型组大鼠肠黏膜TLR4、NF-κBp65、Tollip的表达情况。结果: TLR4、NF-κBp65在结肠炎组肠黏膜中的表达高于正常对照组(TLR4:0.376±0.029, 0.215±0.049, t= 2.731, P=0.013;NF-κBp65:0.746±0.049, 0.206 ±0.063, t=6.055, P=0.000),与大体形态损伤评分及组织学损伤评分呈正相关(TLR4:r=0.754, r=0.866; NF-κBp65:r=0.548, r=0.919);Tollip mRNA在正常组及模型组表达无明显差异(Tollip:0.288±0.050, 0.140±0.046, t=1.993, P=0.061);Tollip蛋白在结肠炎组肠黏膜固有层的表达高于正常组;Tollip的表达与大体形态损伤评分及组织学损伤评分呈负相关(Tollip:r=-0.497, r=-0.551)结论:Toll样受体与负性调控因子Tollip的表达失衡参与了IBD的发病机制。  相似文献   
3.
目的 探讨人食管鳞状细胞癌中Tollip对Src家族酪氨酸激酶Fyn表达的负调控机制.方法 收集3例新鲜食管鳞状细胞癌组织(ESCC)和食管正常黏膜上皮组织(UNR),采用免疫印迹法分析Tollip蛋白表达水平的变化.同时转染人Tollip质粒DNA人TE1细胞株中观察其对Fyn表达的影响.结果 免疫印迹结果 显示食管鳞癌组织Tollip蛋白表达低于食管正常黏膜组织.转染Tollip质粒DNA可以降低人食管鳞状细胞癌TE1细胞中Fyn的表达.结论 Tollip可能是人食管鳞状细胞癌中Src家族酪氨酸激酶ryn的负调控因子,在食管鳞状细胞癌的发生发展过程中起重要作用.
Abstract:
Objective To determine the relationship between Src family tyrosine kinases Fyn expression and Toll-interacting protein ( Tollip ) in human esophageal squamous cell carcinoma ( ESCC ).Methods The Tollip expression was detected in 3 cases of ESCC and compared to the unremarkable epithelium by Western blotting. Tollip plasmid DNA ( 1 μg) was transfected into TE1 cells and the Fyn/Tollip expression was examined by Western blotting. Results The Tollip expression level was lower in ESCC group than in UNR group. Tollip decreased Fyn protein expression in TE1 cells. Conclusion Tollip may act as a negative regulator of Fyn in human ESCC, and play an important role in human ESCC progress.  相似文献   
4.
5.
目的探讨Toll样受体4(TLR4)及Tollip蛋白在大肠癌发生、发展过程中的作用。方法采用免疫组化SP法检测TLR4和Tollip蛋白在51例大肠癌癌组织和20例癌旁正常组织中的表达,并分析两者与大肠癌临床分期、病理分级的相关性。结果TLR4及Tollip蛋白在大肠癌组织中的表达显著强于癌旁正常组织,且两者表达随肿瘤临床病理分期进展及病理分级降低而升高(P〈0.01)。结论TLR4、Tollip蛋白在大肠癌发生、发展过程中发挥一定免疫作用,可作为判断大肠癌进展程度的参考指标。  相似文献   
6.
Apoptotic signal transduction pathways in diabetes   总被引:14,自引:0,他引:14  
Failure of insulin producing pancreatic beta-cells is a common characteristic of type 1 (insulin-dependent) and type 2 (insulin non-dependent) diabetes mellitus. Accumulating evidence suggests that programmed cell death (apoptosis) is the main form of beta-cell death in these disorders. The beta-cell is particularly sensitive to apoptotic stimuli due to the inherent features of the specialized beta-cell phenotype. In type 1 diabetes anti-beta-cell autoimmune reactivity delivers the apoptotic signals in the form of inflammatory mediators or T-cell effectors. In type 2 diabetes, the metabolic derangement is associated with production of inflammatory mediators in insulin-sensitive tissues leading elevated levels of circulating inflammatory mediators such as IL-6 and TNF. Further glucose has been suggested to induce beta-cell apoptosis via the induction of beta-cell synthesis of IL-1 which via autocrine action may elicit signalling cascades analogous to those seen in beta-cell destruction in type 1 diabetes. Considering the apparent importance of IL-1-beta signalling in beta-cell failure in both type 1 and type 2 diabetes, we here review the modulatory effect exerted on IL-1signalling by cellular characteristics related to the specialized beta-cell phenotype. We conclude that beta-cell differentiation signals (Pdx-1), glucose metabolism, calcium handling as well as regulation of naturally occurring inhibitors of cytokine signalling contribute to sensitize the beta-cell to apoptotic stimuli. We hypothesize that immunological stimuli in type 1 diabetes and metabolic/inflammatory signals in type 2 diabetes converge on common signalling pathways leading to beta-cell failure and destruction in these two diseases.  相似文献   
7.
Objective. Growing evidence indicates that innate immunity, including toll-like receptor (TLR) signalling, plays a role in inflammatory bowel disease (IBD). This may also apply in the case of TLR-8, which has recently been shown to reverse the immunosuppressive function of regulatory T cells. However, the role of TLR-8 in IBD is currently unknown, and therefore we investigated the expression of TLR-8 and its natural antagonist, Tollip, in normal and inflamed human gut, and examined whether the receptor is functionally active. Methods. TLR-8 and Tollip mRNA expression were measured in colonic epithelial cells (CEC) and lamina propria mononuclear cells (LPMNC) by quantitative polymerase chain reaction. TLR-8 protein expression was visualized in whole biopsy specimens by indirect immunofluorescence microscopy. Cellular localization of TLR-8 protein was assessed by immuno-electron microscopy. IL-8 secretion was measured by ELISA after stimulation with TLR-8 ligand. Results. TLR-8 mRNA and protein expression were substantially up-regulated in CEC from inflamed mucosa from patients with ulcerative colitis (~350-fold, p<0.01) and Crohn's disease (~45-fold, p<0.05) compared to controls. TLR-8 proteins resided on the luminal surface membrane and in intracellular organelles. Tollip was not increased in CEC from IBD patients. CEC from normal mucosa responded to TLR-8 stimulation by secreting IL-8. TLR-8 was expressed only on the mRNA level in LPMNC with no differences between IBD patients and controls. Conclusion. Expression of TLR-8, but not Tollip, is highly up-regulated in the colonic epithelium from patients with active IBD. Since the receptor is functionally active, our data suggest that TLR-8 signalling is important in the pathogenesis of IBD.  相似文献   
8.
Many functional details of the piscine Toll-like receptor (TLR) signal-mediated activation of immune defense are still elusive. We used an established reconstitution system of mammalian TLR signaling to examine if this system would allow for pathogen-dependent promoter activation of the serum amyloid A (SAA)-encoding gene from rainbow trout (Oncorhynchus mykiss) and if the key mediators MyD88 and Tollip from trout can functionally substitute for their mammalian orthologues. Cells of the established human embryonic kidney line HEK-293 were transiently co-transfected with vectors expressing bovine TLR2 or TLR4 factors and a reporter gene driven by the promoter of the trout SAA gene. Escherichia coli stimulation increased reporter gene expression more than 3-fold. Deletion series and point mutations identified in the proximal SAA promoter a composite overlapping binding site for NF-κB and CEBP factors as crucial for promoter activation. Overexpression of NF-κB p65, but not of p50 or different members of the CEBP factor family proved this factor as an essential driver for SAA expression. Overexpression of a transdominant-negative mutant of the trout MyD88 factor reduced TLR-mediated SAA promoter activation confirming functional conservation of its TIR domain. Overexpression of the Tollip factor from trout also quenched TLR-mediated NF-κB and TLR4-mediated SAA promoter activation. The MyD88 mutant and Tollip expression studies confirm the functional homology of both piscine factors and their mammalian counterparts. We provide for the first time evidence that also the Tollip-mediated negative loop of TLR signaling may be conserved in non-mammalian organisms.  相似文献   
9.

Background

Green tea polyphenol epigallocatechin-3-gallate (EGCG) has the potential to impact a variety of inflammation-related diseases; however, the anti-inflammatory action of EGCG in endothelial cells has not been understood. Recently, we demonstrated that the 67-kDa laminin receptor (67LR) acts as a cell-surface EGCG receptor.

Aim

This research was carried out to clarify the molecular basis for the down-regulation of toll-like receptor 4 (TLR4) signal transduction by EGCG in lipopolysaccharide (LPS)-stimulated endothelial cells.

Results

RNAi-mediated silencing of 67LR resulted in an abrogation of the inhibitory action of EGCG on the LPS-induced activation of downstream signaling pathways. Also, we found that EGCG induced a rapid upregulation of Toll-interacting protein (Tollip), a negative regulator of TLR signaling, through 67LR in endothelial cells. RNAi-mediated silencing of Tollip impaired the TLR4 signaling inhibitory activity of EGCG. Additionally, silencing of Tollip resulted in an abrogation of the inhibitory action of EGCG on the LPS-induced expressions of cell-associated adhesion molecules, such as ICAM-1 and VCAM-1.

Conclusion

Taken together, these novel findings provide new insights into an understanding of negative regulatory mechanisms of the TLR4 signaling pathway and effective therapeutic intervention for the treatment of inflammatory disease.  相似文献   
10.
Huntington disease (HD) is caused by the expansion of polyglutamine (polyQ) repeats in the amino-terminal of hungtintin (htt). PolyQ-expanded htt forms intracellular ubiquitinated aggregates in neurons and causes neuronal cell death. Here, utilizing a HD cellular model, we report that Tollip, an ubiquitin binding protein that participates in intracellular transport via endosomes, co-localizes with and stimulates aggregation of polyQ-expanded amino-terminal htt. Furthermore, we demonstrate that Tollip protects cells against the toxicity of polyQ-expanded htt. We propose that association of Tollip with polyubiquitin accelerates aggregation of toxic htt species into inclusions and thus provides a cell protective role by sequestration.  相似文献   
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